1. Field of the Invention
This invention relates to a biocompatible, osteoinductive/osteoconductive, collagen/demineralized human bone composite material that may be used in a fluid injectable or rehydratable freeze-dried paste form, and to a process for making this material. The composition possesses the attributes of being deliverable as a mixture in a fluidized state or as a mixture in a gel state, of being compatible with tissues surrounding the site(s) of its application, of promoting cellular infiltration from adjacent osseous tissues following application, and of possessing osteoinductive/osteoconductive properties such that it will ultimately be remodeled and the application site returned to a mineralized, hard tissue.
2. Discussion of Background Information
The induced formation of new bone through the use of various matrix material has been discussed in the past. In this regard, various matrix materials and various combinations of the matrix materials have been formulated into implantable, as well as injectable forms.
One group of technology uses collagen, demineralized bone or a combination of the two to form implantable sponges, bandages or prostheses. For instance, U.S. Pat. No. 4,394,370 describes the fabrication of a sponge suitable for in vivo implantation in osseous defects. In particular, the sponge is fabricated using a complex of reconstituted collagen and demineralized human bone particles or reconstituted collagen and a solubilized bone morphogenetic protein. Specifically, the sponge described in U.S. Pat. No. 4,394,370 utilizes more than 50% of nonhuman microcrystalline collagen in conjunction with demineralized bone powder (particle size less than 75 microns) and glutaraldehyde to cross-link the collagen.
U.S. Pat. No. 4,412,947, describes a process for preparing a porous collagen sheet material used for wound healing. The device is an absorbent dressing having a bulk density of 0.005 to 0.0065 g/cm.sup.3 made by freeze-drying a dispersion of particulate xenogeneic collagen in a weak aqueous organic acid solution.
Another example of an implant is U.S. Pat. No. 5,110,604 which describes a collagen implant useful as a wound healing matrix or sustained release depot for administration of bioactive agents. The implant utilizes a commercially available atelopeptide bovine skin collagen, that is chemically cross-linked. Moreover, the invention provides for the addition of "bioactive additives" such as fibroblast growth factor.
Other patents describing nonhuman collagen sponges are U.S. Pat. Nos. 3,742,955, 3,810,473, 4,515,637, and 4,578,067.
Another group of technology uses collagen and a mineral component to form the implantable material. For example, U.S. Pat. No. 5,001,169 describes a composition suitable for inductive bone implants. The composition comprises a mixture of a purified form of osteogenic factor with a carrier. In particular, the carrier comprises at least 75% of a mineral component such as various forms of calcium phosphate--i.e., hydroxyapatite or tricalcium phosphate--and the rest is fibrillar collagen, non-fibrillar collagen or a combination of the two. The resulting implants are sufficiently hypoimmunogenic to be effective when implanted in xenogeneic hosts.
Additionally, U.S. Pat. No. 5,123,925 describes a formable composition comprised of 2-40% of reconstituted fibrillar atelopeptide collagen and 60-98% calcium phosphate mineral. This patent discusses use of gamma irradiation on collagen/mineral mixtures to improve both biological and handling properties where cross-linking of the mixture by irradiation was enhanced.
Moreover, U.S. Pat. No. 4,314,380 utilizes a mineral backbone, prepared by the treatment of animal bone to remove all organic materials, which is then coated with an atelopeptide collagen. In addition, Japanese Application J58/058041, published Apr. 6, 1983 discloses a spongy porous calcium phosphate material having pores treated with atelopeptide collagen. Further, European patent No. 0 030 583, published Jun. 24, 1981, discloses use of a collagen fleece in admixture with hydroxyapatite in bone repair. The collagen material is a commercial product obtained from animal hides by proteolytic digestion. Finally, U.S. Pat. No. 4,992,226 provides for a process for coating the pores of a mineral matrix with collagen by pumping collagen through the molded matrix. The resulting coated matrix could be used as a prosthesis in bone repair (see also U.S. Pat. No. 4,795,467.)
Yet another group of patents discloses the bone forming material as being injectable. For example, U.S. Pat. No. 4,424,208 discloses an implant material comprised of a dispersion of solid elastic particles of cross-linked atelopeptide collagen and reconstituted atelopeptide collagen fibers in a physiologically aqueous carrier. While this material is injectable through medium gauge needles, its extrusion and intrusion properties are poor.
Another patent disclosing injectable forms of various collagen and bone products to induce bone formation is U.S. Pat. No. 4,440,750. This patent describes the use of a plastic dispersion of demineralized bone powder and reconstituted native nonhuman atelopeptide collagen fibers or tropocollagen in a continuous aqueous phase. The continuous phase has a substantially physiologic pH and ionic strength and is said to be used in repair or in reconstruction of bone by injection or implantation at the repair or reconstruction site. The patent describes the collagen as either retaining its telopeptide or preferably the collagen can be without its telopeptide. Further, the collagen is prepared from the skin of a variety of mammalian sources (xenogeneic), and therefore the collagen is composed of type I and type III xenogeneic collagen. Moreover, the demineralized bone powder is also xenogeneic (preferably bovine or porcine), and is demineralized via a process which provides a heterogeneous demineralized bone product.
Still a further patent that discloses an injectable material is U.S. Pat. No. 4,789,663 which describes a method of repairing bone defects using a suspension containing purified atelopeptide, reconstituted, fibrillar skin collagen or bone collagen powder or mixtures thereof. In this regard, the suspensions provide a matrix for conductive growth of bone into the defect. In addition, the patent describes the formation of the skin collagen into freeze dried "mats". The patent describes the use of bone derived collagen produced from demineralized bone, and its collagen component is primarily type I collagen. In particular, the collagen is removed from the bone using a non-collagenase protease, such as trypsin, and then formed into a powder. The described method of collagen preparations, i.e. using a protease such as trypsin, has the effect of destroying factors such as bone morphogenetic proteins (BMP) responsible for inductive repair osteogenesis, as well as cleaving the telopeptides from the collagen which is necessary for intramolecular cross-linking of type I collagen.
An additional example of an injectable aqueous suspension of biomaterials is disclosed in U.S. Pat. No. 4,803,075. This patent describes a collagen which is cross-linked, and contains a biocompatible fluid lubricant such as glycogen, or maltose, and it is disclosed that the inclusion of the lubricant significantly improved the intrusion of the suspension into soft tissue.
A further example of an injectable composition for inductive bone repair is U.S. Pat. No. 4,863,732, which discloses the use of aqueous suspensions of fibrillar atelopeptide collagen, prepared from a nonhuman source, and osteogenic factor(s) isolated from demineralized bone. Even more specifically, the osteogenic factor(s) are isolated using dissociative solvents and purified by gel filtration column chromatography (S-200) to obtain the low molecular weight (&lt;35,000 daltons) proteins.
A still further injectable composition is U.S. Pat. No. 5,073,373 which describes a flowable, injectable, demineralized bone powder composition provided for use in surgical bone repair. The composition utilizes a biocompatible liquid synthetic organic material as the carrier for the demineralized bone. In this regard, liquid refers to either organic materials which, in the pure or highly concentrated state and at ambient temperature, are flowable liquids; or organic materials which, in the pure or concentrated state and at ambient temperature, are normally solid, but dissolved in a suitable solvent, such as water, ethanol, etc., can be provided in liquid form. In particular, suitable organic materials (carriers) include liquid polyhydroxy compounds and their esters, polysaccharides, surface active agents, and the like. Specific polyhydroxy compounds of the foregoing type include glycerol, as well as its monoesters and diesters derived from low molecular weight carboxylic acids, e.g., monacetin and diacetin. In particular, glycerol is the preferred liquid organic carrier.
U.S. Pat. No. 5,073,373 further discloses that a variety of substances can be introduced into the demineralized bone particles used in this preparation and include, for example, antibiotics, amino acids, vitamins, angiogenic drugs, collagen lattices, biologically active components such as bone morphogenetic protein (BMP), and mesenchymal elements.
European Patent number 0 495 284 A1 also describes an injectable composition as a surface adherent osteogenic composition derived from demineralized bone. In this regard, the demineralization of bone is further processed by acid-promoted cleavage of the bone collagen matrix with 2N hydrochloric acid at elevated temperatures, most preferably from about 40.degree. C. to about 55.degree. C. The acid degraded bone derived collagen is obtained in a denatured state wherein the fibrillar structure of the collagen has been altered.
The patent discloses that the collagen preparation can be used as the carrier for a host of medically/surgically useful substances including insoluble solids such as demineralized bone powder.
Additional documents disclosing injectable solutions of biomaterials include U.S. Pat. Nos. 3,949,073, and 4,582,640.